A pharmacovigilance study on clinical factors of active vitamin D3 analog-related acute kidney injury using the Japanese Adverse Drug Event Report Database

Acute kidney injury (AKI) due to vitamin D therapy for osteoporosis is encountered in clinical practice, but epidemiological studies are scarce. We aimed to determine the association between AKI and vitamin D therapy and to identify risk factors for AKI using the Japanese Adverse Drug Event Report database. We used reporting odds ratios (RORs) to detect signals and evaluate risk factors using multiple logistic regression analysis. Among 298,891 reports from April 2004 to September 2023, 1071 implicated active vitamin D3 analogs as suspect drugs for adverse events. There was a significant association between AKI and active vitamin D3 analogs (ROR [95% confidence interval {CI}], eldecalcitol: 16.75 [14.23–19.72], P < 0.001; alfacalcidol: 5.29 [4.07–6.87], P < 0.001; calcitriol: 4.46 [1.88–10.59], P < 0.001). The median duration of administration before AKI onset was 15.4 weeks. Multiple logistic regression analysis showed a significant association between AKI and age ≥ 70 years (odds ratio [95% CI], 1.47 [1.04–2.07]; P = 0.028), weight < 50 kg (1.55 [1.12–2.13]; P = 0.007), hypertension (1.90 [1.42–2.54]; P < 0.001), and concomitant use of nonsteroidal anti-inflammatory drugs (1.58 [1.10–2.25], P = 0.012) and magnesium oxide (1.96 [1.38–2.78]; P < 0.001). Our results suggest that active vitamin D3 analogs are associated with AKI development. Physicians prescribing these medications to patients with risk factors should consider the possibility of AKI, especially during the first 6 months.

Although the estimated incidence rate of acute kidney injury (AKI) in the general population has not been established, 9.6-12.2% of hospitalized patients are reported to develop AKI 1,2 .The incidence of AKI is increasing worldwide 3 .Additionally, 19-25% of AKI is induced in association with medications 4,5 .AKI may be a risk factor for long-term complications, such as end-stage renal failure and mortality 6,7 .Therefore, identifying clinical factors associated with the occurrence of AKI for individual medications is important for implementing preventive strategies in the clinical setting.
Although AKI due to vitamin D therapy, a treatment for osteoporosis, is often encountered in clinical practice, research on this topic is limited to case reports [8][9][10] and case series [11][12][13][14][15] .There have been few epidemiological studies on AKI due to vitamin D therapy.Vitamin D drugs may induce hypercalcemia by promoting intestinal calcium absorption [16][17][18][19] .Although the pathogenesis of AKI owing to hypercalcemia is not fully understood, the following mechanisms have been reported: (1) circulating volume depletion occurs as a result of hypercalcemia, causing impaired renal concentrating capacity due to inhibition of sodium and chloride reabsorption in the ascending limb of Henle's loop and a reduced response of antidiuretic hormone in collecting ducts 20,21 ; (2) direct renal vasoconstrictive effects due to hypercalcemia 22 ; and (3) tubulointerstitial injury due to calcium deposition 23,24 .
Vitamin D drugs are not generally the first choice for treating osteoporosis.However, sufficiency of vitamin D is a prerequisite for treating osteoporosis according to the National Osteoporosis Federation guidelines 25 .Furthermore, osteoporosis is still treated with vitamin D drugs not only because of vitamin D deficiency but also to avoid side effects such as osteonecrosis of the jaw with bisphosphonates.
Information on the occurrence of AKI associated with the three vitamin D drugs covered by insurance in Japan is primarily focused on eldecalcitol, which was launched in 2011; reports on the association with the other two drugs are scarce.Furthermore, a post-marketing observational study conducted 1 year after the launch of eldecalcitol reported a relatively low incidence of renal impairment adverse events (AEs) at 0.27% 26 .Additionally, clinical factors related to the occurrence of AKI as an AE with use of vitamin D drugs remain unknown.
Spontaneous reporting systems of adverse drug reactions, including the Japanese Adverse Drug Event Report (JADER) database and US Food and Drug Administration (FDA) adverse event reporting system (FAERS) have been used in pharmacovigilance analyses [27][28][29][30][31] .These databases are useful in detecting rare AEs or revealing new AEs by identifying drug-reaction pairs that occur with a significant disproportion compared with all other pairs 32,33 .
In this study, we aimed to determine the association between AKI and vitamin D drugs and to identify the risk factors for developing AKI using a large nationwide database on AEs.

Data extraction and patients' characteristics
Among 298,891 cases in the final analysis, there were 1071 cases of AEs with active vitamin D 3 analog use, including 621 cases for eldecalcitol, 408 cases for alfacalcidol, and 42 cases for calcitriol.Of these 1071 cases, 309 cases involved AKI, among which 236 cases involved the use of eldecalcitol, 67 the use of alfacalcidol, and 6 the use of calcitriol.Table 1 shows a comparison of patient characteristics between those with AKI and those with other AEs associated with active vitamin D 3 analog use.Cases with AKI tended to involve a higher proportion of female individuals than cases with other AEs.Additionally, cases of AKI included a significantly higher proportion of older patients (≥ 70 years) and those with low body weight (< 50 kg) (P < 0.001) than cases of other AEs.Cases of AKI included a significantly higher proportion of patients with a medical history of hypertension than cases of other AEs (P < 0.001); there was no difference in CKD, diabetes, or heart failure between the two groups.Additionally, higher proportions of concomitant NSAID and RASI use were observed in cases of AKI than in cases of other AEs (both P = 0.001).Similarly, cases of AKI included a significantly higher proportion of concomitant use of magnesium oxide than those involving other AEs (P < 0.001).

Logistic regression analysis of risk factors for active vitamin D 3 analog-related AKI
Table 2 shows the results of multiple logistic regression analysis for factors associated with AKI in users of active vitamin D

Discussion
To the best of our knowledge, this is the first study to assess the risk of developing AKI in vitamin D drug users and to investigate associated clinical factors using a nationwide large-scale database.Eldecalcitol, alfacalcidol, and calcitriol showed significant signals associated with the development of AKI.Furthermore, older age  The association of older age and low body weight with AKI in users of active vitamin D 3 analogs is consistent with findings in previous case series 11,12,14 .Aging degenerates the kidney structure and reduces renal autoregulatory capacity, which increases susceptibility to acute injury 34 .Specifically, renal vasoconstriction under hypercalcemia may be more likely in older patients because of a high sensitivity to vasoconstriction factors, leading to a subsequent severe decrease in the glomerular filtration rate 35 .Another change in the aging kidney is decreased renal tubular sodium reabsorption 36 .Additionally, because of a decrease in total body water 37 , older patients may be less tolerant to circulating volume depletion under hypercalcemia.Although previous studies have suggested that obesity is a potential risk factor for AKI in several clinical situations 38 , we showed that low body weight was a risk factor for active vitamin D 3 analog-related AKI.Sensitivity to volume depletion under hypercalcemia could enhance the onset of AKI because patients with a low body weight have less total volume.
In this study, hypertension, as well as the concomitant use of NSAIDs and magnesium oxide, were significantly associated with developing AKI.The association between hypertension and the development of AKI has been reported in populations including older people 39 and patients undergoing cardiothoracic surgery 40 or transcatheter aortic valve implantation 41 .Hypertension may predispose to AKI under hypercalcemia because it causes decreased autoregulation of renal blood flow 42,43 as well as renal arteriosclerosis and tubulointerstitial injury 44,45 .NSAIDs attenuate renal vasodilation and cause AKI by indirectly suppressing the production of prostaglandins via the inhibition of cyclooxygenase 46,47 .If the circulating blood volume is reduced owing to hypercalcemia, NSAIDs may induce a marked reduction in renal blood flow, increasing the likelihood of AKI occurrence.Magnesium oxide is reported to be associated with higher blood calcium levels in patients hospitalized with vitamin D-induced AKI 11 Magnesium oxide intake can lead to metabolic alkalosis and increased renal tubular calcium reabsorption, potentially resulting in AKI 48,49 .
RASIs, loop diuretics, thiazide and thiazide-related diuretics, CKD, diabetes, and heart failure were not associated with developing AKI in the present study.Although we predicted that RASIs would induce AKI under hypercalcemia, similar to its induction under hypovolemia 50 , we found no association between active vitamin D 3 analogs and AKI.Contrary to our predictions, RASIs might have offset the increased risk of AKI under hypercalcemia in this study, considering its reported potential to protect against AKI in patients aged 75 years and older 39 and in preoperative patients 51,52 .Additionally, because loop diuretics increase urinary calcium excretion and are also used with saline to treat hypercalcemia 53 , we expected them to show a negative association with AKI.However, although loop diuretics may improve hypercalcemia, as mentioned above, they also may contribute to AKI by reducing circulating volume.Therefore, the lack of an association between loop diuretics and AKI in the present study might be attributed to these dual effects.Furthermore, thiazide and thiazide-related diuretics, which decrease urinary calcium excretion 53 , as well as CKD, heart failure, and diabetes, showed no association with AKI.Further investigation is required to determine their mechanism of action.
Although female sex was significantly associated with AKI in univariate logistic regression analysis, this significance was lost in multivariate analysis.There is limited research on sex differences in the risk of AKI, and the association between sex and AKI varies according to previous reports.Several reports have suggested that drug-induced AKI poses a higher risk in female individuals 37,54 whereas other reports have shown that male hospitalized patients have a higher risk of AKI 55,56 .The possibility of female users of active vitamin D 3 analog having a higher risk of AKI onset has been previously discussed 11 .This higher risk in female individuals may be owing to the higher prevalence of osteoporosis in women 57 and the corresponding larger proportion of female users of vitamin D 3 analogs.
In this study, the median duration of vitamin D 3 analog administration prior to AKI onset was 15.4 weeks.In a previous case series 14 , the average duration of vitamin D 3 administration was 9 weeks.Because that case series included cases involving intramuscular injection in addition to oral administration, the difference in the route of vitamin D administration between that case series and the present study may have affected the difference in duration before AKI onset between studies.
A strength of this study is the identification of clinical factors associated with AKI in active vitamin D 3 analog users using a large national database.Although AKI caused by vitamin D drugs is frequently experienced in clinical practice, few epidemiological studies have examined the factors involved in this association.Therefore, the clinical factors suggested in previous case reports and case series were assessed in this study.
This study has several limitations.First, because the JADER database only includes cases in which AEs occurred, we were unable to include information on patients in whom no AEs occurred.Therefore, we could not calculate the incidence of AKI.Second, because the JADER database comprises spontaneous reports of AEs, several biases, such as reporting bias, underreporting, and missing data, may have been present and affected the RORs.Therefore, although the ROR is a well-established indicator in pharmacovigilance studies 58 , comparing the risk of AEs between different drugs based solely on ROR values may be unsuitable.Furthermore, because alfacalcidol and calcitriol are also prescribed for other diseases, including hypoparathyroidism, the drug indication might affect our results.Third, the JADER database only includes AEs occurring in Japan; therefore, it may be difficult to extrapolate the findings of this study to populations in other countries.Fourth, the risk of AKI associated with vitamin D 3 analogs covered by insurance in Japan for osteoporosis treatment in this study could potentially be overestimated owing to the following factors: (1) the types of vitamin D drugs for osteoporosis frequently used in Japan and other countries differ; (2) the diagnostic criteria for osteoporosis in Japan 59 not only include the T-score based on the World Health Organization definition 60 but also young adult mean values and the presence of fractures, which could potentially lead to the initiation of treatment.Additionally, warnings were issued by the PMDA for one vitamin D 3 analog regarding hypercalcemia.Therefore, the findings of this study may need to be validated using overseas databases, such as the FAERS.Fifth, the clinical background www.nature.com/scientificreports/information on patients that was available in the JADER database was limited.This might have affected the results with poor calibration and discrimination based on logistic regression, indicating the presence of other risk factors associated with the occurrence of AKI in vitamin D users.Sixth, female patients predominated in both groups in our study.This predominance might have affected our regression results.Seventh, in view of the finding that magnesium oxide is a potential factor for AKI, the AKI might be due to hypercalcemia.However, since the JADER database is secondary data, it was hard to include blood calcium levels and the accurate doses of active vitamin D 3 analogs in our analysis.Verifying the results of this study using electronic health care databases, including claims databases and electronic medical records databases that include high-volume data and high-quality information, may address these limitations.
In conclusion, the results of this study suggest that active vitamin D 3 analogs may increase the risk of AKI.When administering active vitamin D 3 analogs to patients with specific characteristics, such as older age, low body weight, hypertension, and concomitant use of NSAIDs and magnesium oxide, careful attention should be paid to acute deterioration of renal function, especially during the first 6 months.

Data source
We used the JADER database in this study.This database is an anonymized, open-access repository provided on the Pharmaceuticals and Medical Devices Agency (PMDA) website 61 .The JADER database contains spontaneous reports of drug-related AEs in Japan since April 2004.This database comprises four data tables: DEMO (patient demographic information), DRUG (drug information), REAC information), and HIST (medical history).In the DRUG table, the involvement of drugs in AEs is categorized into three categories of suspected drugs, concomitant drugs, and interacting drugs.

Data collection
Data from April 2004 to September 2023 were downloaded from the PMDA website.On the basis of previous reports [62][63][64] , cases aged < 20 years, those with missing or unknown information on sex, age, and body weight, and those with age recorded in non-numeric formats (e.g., pediatric, adult, and older), were excluded.We also excluded cases categorized only as having concomitant or interacting drugs, those with intravenous administration of active vitamin D 3 analogs, and those with duplicate use of active vitamin D 3 analogs.Among 857,168 cases, the final analysis included data of 298,891 cases (Fig. 2).

Definition of target and concomitant drugs
Active vitamin D 3 analogs, nonsteroidal anti-inflammatory drugs (NSAIDs), renin-angiotensin system inhibitors (RASIs; e.g., angiotensin receptor blockers and angiotensin-converting enzyme inhibitors), loop diuretics, thiazide and thiazide-related diuretics, and magnesium oxide were defined according to the drug names in the Kyoto Encyclopedia of Genes and Genomes drug database 65 , with reference to a previous report 64 .For the purpose of this study, vitamin D 3 drugs were limited to active vitamin D 3 analogs that are covered by insurance for the treatment of osteoporosis.Aspirin is classified as an NSAID in the Kyoto Encyclopedia of Genes and Genomes drug database.However, because aspirin is administered as an antiplatelet agent, it was not included in the category of NSAIDs in this study.The generic names of all drugs used in the analysis are shown in Supplementary Table 1.

Definition of AEs and comorbidities
AEs and comorbidities in the JADER database are coded using preferred terms (PTs) in the Medical Dictionary for Regulatory Activities (MedDRA)/Japanese version 26.1.When searching for specific diseases in the JADER database, we used standardized MedDRA Queries (SMQs), which groups MedDRA terms, generally consisting www.nature.com/scientificreports/ of PT-level terms related to a defined medical condition or area of interest 66 .AKI was defined using the PTs classified as "acute renal failure" in the SMQs, as reported previously 27,64 .Similarly, CKD was identified using the PTs classified as "chronic kidney disease, " "kidney failure", or "dialysis", in accordance with previous studies 67,68 .Hypertension, diabetes, and heart failure were also defined using the PTs classified as "hypertension", "hyperglycemia/new onset diabetes mellitus", and "cardiac failure", respectively.PTs used for the identification of each disease are shown in Supplementary Table 2.

Definition of time to onset of AKI
The time to onset of AKI was calculated for reports of AKI AEs due to use of active vitamin D 3 analogs in which the date of onset of the AE and date of initiating administration were listed in years, months, days, or years and months, as previously reported 69,70 .The time to onset of AEs used in the analysis was limited to 730 days (2 years).The number of days to onset of AEs was calculated as follows: (date of AE onset) − (date of starting administration) + 1 70 .

Statistical analysis
We conducted disproportionality analysis to detect target drug-related AKI signals.We calculated the reporting odds ratio (ROR) using a two-by-two contingency table, as described previously 71,72 .In this study, we chose the full dataset comparator for signal detection 73 because this comparator reportedly has the advantage of reducing the impact of reporting biases compared with restricted comparators, including an active comparator.The calculation method of RORs and 95% confidence intervals (CIs) is shown in Supplementary Table 3.A significant signal was detected when the lower limit of the 95% CI for the ROR was > 1.Multiple logistic regression using the forced-entry method was conducted to identify the factors associated with AKI among users of active vitamin D 3 analogs.The covariates included sex 11 , age (< 70 or ≥ 70 years) 11,14 , body weight (< 50 or ≥ 50 kg) 12 , chronic kidney disease (CKD) 14 , and concomitant use of NSAIDs 11,12 , RASIs 11,12 , loop diuretics 11 , thiazide and thiaziderelated diuretics, and magnesium oxide 11 , which are reported or considered to be associated with the onset of AKI with vitamin D therapy.Moreover, hypertension, diabetes, and heart failure were included as well-known risk factors for AKI 39,63,74,75 .We assessed the discrimination and calibration of the logistic model using the area under the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit test, respectively.Two-sided P values < 0.05 were considered statistically significant.Statistical analyses were performed using R version 4.

Fig. 1 .
Fig. 1.Histogram of the number of weeks from the date of initiating active vitamin D 3 analogs to the date of onset of adverse events of acute kidney injury.

Fig. 2 .
Fig. 2. Flowchart of the construction of the dataset used in our study.JADER Japanese Adverse Drug Event Report.

Table 1 .
Comparison of patients' characteristics between those with AKI and those with other adverse events associated with active vitamin D 3 analog use.AKI acute kidney injury, AE adverse event, NSAIDs nonsteroidal anti-inflammatory drugs, RASIs renin-angiotensin system inhibitors.

Table 2 .
Multiple ≥ 70 years), low body weight (< 50 kg), a medical history of hypertension, and concomitant use of NSAIDs and magnesium oxide were risk factors associated with the development of AKI in active vitamin D 3 analog users with AE reported to PMDA.